A systematic review and meta-analysis of the 2007 WCRF/AICR score in relation to cancer-related health outcomes.

BACKGROUND: We conducted a systematic literature review and meta-analysis of observational studies investigating adherence to the 2007 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) lifestyle recommendations for cancer prevention and health outcomes. PATIENTS AND METHODS: We searched PubMed and the in-house database of the WCRF Continuous Update Project for publications up to June 2019. Cross-sectional studies were only narratively reviewed given their heterogeneity while findings of cohort/case-control studies were synthesized in umbrella reviews and meta-analyses. Summary relative risks (RRs) and 95% confidence intervals (CI) were estimated using a random-effects model when at least two studies reported results on a specific outcome. RESULTS: Thirty-eight articles (17 prospective, 8 case-control, and 13 cross-sectional studies) were included. The summary RR per each point increment in the 2007 WCRF/AICR score was 0.90 (95% CI: 0.87-0.93, n = 11) for breast cancer, regardless of hormone receptor and menopausal status, 0.86 (95% CI: 0.82-0.89, n = 10) for colorectal cancer, and 0.93 (95% CI: 0.89-0.96, n = 2) for lung cancer risk. No statistically significant associations were reported for prostate (n = 6) and pancreatic cancers (n = 2). Adherence to the recommendations was associated with lower overall mortality (RR = 0.90, 95% CI 0.84-0.96, n = 3) and cancer-specific mortality (RR = 0.91, 95% CI 0.89-0.92; n = 3) in healthy populations, as well as with higher survival in cancer patients (n = 2). In cross-sectional studies, a healthier plasma marker profile and lower cancer risk factors in the general population and a better health status and quality of life in cancer patients/survivors were reported. CONCLUSIONS: Adhering to the 2007 WCRF/AICR recommendations is associated with lower risks of cancer incidence, namely breast and colorectal cancers, and mortality. Primary prevention of cancer should emphasize modification of multiple lifestyle factors. Upcoming studies examining the recently updated 2018 guidelines will further clarify such associations.

Self-reported and measured anthropometric data and risk of colorectal cancer in the EPIC-Norfolk study.

BACKGROUND: Epidemiological studies have shown inconsistent results for the association between body size and colorectal cancer (CRC) risk. Inconsistencies may be because of the reliance on self-reported measures of body size. OBJECTIVE: We examined the association of self-reported and directly assessed anthropometric data (body height, weight, body mass index (BMI), waist, hip, waist-to-hip ratio (WHR) and chest circumference) with CRC risk in the EPIC-Norfolk study. DESIGN: A total of 20,608 participants with complete self-reported and measured height and weight and without any history of cancer were followed up an average of 11 years, during which 357 incident CRC cases were recorded. Hazard Ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. RESULTS: After adjustment for confounders, HRs among women in the highest quintile of the body size measure relative to the lowest quintile showed that measured height (HR=1.98, 95% CI=1.19-3.28, P (trend)=0.009), measured waist circumference (HR=1.65, 95% CI=0.97-2.86, P (trend)=0.009) and measured WHR (HR=2.07, 95% CI=1.17-3.67, P (trend)=0.001) were associated with increased CRC risk. Associations using corresponding self-reported measures were attenuated and not statistically significant. Conversely, the association of BMI with CRC risk in women was weaker using measured BMI (HR=1.57, 95% CI=0.91-2.73, P (trend)=0.05) compared with self-reported BMI (HR=1.97, 95% CI=1.18-3.30, P (trend)=0.02). In men no significantly increased CRC risk was observed with any of the anthropometric measures. CONCLUSIONS: Measured height, waist circumference and WHR were associated with CRC risk in women, whereas any significant associations with those measures were attenuated when self-reported data were used.

Alcohol intake and risk of colorectal cancer: results from the UK Dietary Cohort Consortium.

BACKGROUND: Epidemiological studies have suggested that excessive alcohol intake increases colorectal cancer (CRC) risk. However, findings regarding tumour subsites and sex differences have been inconsistent. METHODS: We investigated the prospective associations between alcohol intake on overall and site- and sex-specific CRC risk. Analyses were conducted on 579 CRC cases and 1996 matched controls nested within the UK Dietary Cohort Consortium using standardised data obtained from food diaries as a main nutritional method and repeated using data from food frequency questionnaire (FFQ). RESULTS: Compared with individuals in the lightest category of drinkers (>0-<5 g per day), the multivariable odds ratios of CRC were 1.16 (95% confidence interval (95% CI): 0.88, 1.53) for non-drinkers, 0.91 (95% CI: 0.67, 1.24) for drinkers with 5-<15 g per day, 0.90 (95% CI: 0.65, 1.25) for drinkers with 15-<30 g per day, 1.02 (95% CI: 0.66, 1.58) for drinkers with 30-<45 g per day and 1.19 (95% CI: 0.75, 1.91) for drinkers with >or=45 g per day. No clear associations were observed between site-specific CRC risk and alcohol intake in either sex. Analyses using FFQ showed similar results. CONCLUSION: We found no significantly increased risk of CRC up to 30 g per day of alcohol intake within the UK Dietary Cohort Consortium.

Rates of lipid fluxes in adipose tissue in vivo after a mixed meal in morbid obesity.

OBJECTIVE: Although insulin resistance in obesity is established, information on insulin action on lipid fluxes, in morbid obesity, is limited. This study was undertaken in morbidly obese women to investigate insulin action on triacylglycerol fluxes and lipolysis across adipose tissue. SUBJECTS AND DESIGN: A meal was given to 26 obese (age 35+/-1 years, body mass index 46+/-1 kg m(-2)) and 11 non-obese women (age 38+/-2 years, body mass index 24+/-1 kg m(-2)). Plasma samples for glucose, insulin, triglycerides and non-esterified fatty acids (NEFAs) were taken for 360 min from a vein draining the abdominal subcutaneous adipose tissue and from the radial artery. Adipose tissue blood flow was measured with (133)Xe. RESULTS: In obese vs non-obese: (1) Arterial glucose was similar, but insulin was increased (P=0.0001). (2) Adipose tissue blood flow was decreased (P=0.0001). (3) Arterial triglycerides (P=0.0001) and NEFAs (P=0.01) were increased. (4) Lipoprotein lipase was decreased (P=0.0009), although the arteriovenous triglyceride differences were similar. (5) Veno-arterial NEFA differences across the adipose tissue were similar. (6) NEFA fluxes and hormone-sensitive lipase-derived glycerol output from 100 g adipose tissue were not different. (7) Total adipose tissue NEFA release was increased (P=0.02). CONCLUSIONS: In morbid obesity: (a) hypertriglycerinemia could be attributed to a defect in the postprandial dynamic adjustment of triglyceride clearance across the adipose tissue, partly caused by blunted BF; and (b) postprandially, there is an impairment of adipose tissue to buffer NEFA excess, despite hyperinsulinemia.

Index-based dietary patterns and risk of colorectal cancer: the NIH-AARP Diet and Health Study.

The authors compared how four indexes-the Healthy Eating Index-2005, Alternate Healthy Eating Index, Mediterranean Diet Score, and Recommended Food Score-are associated with colorectal cancer in the National Institutes of Health-AARP Diet and Health Study (n = 492,382). To calculate each score, they merged data from a 124-item food frequency questionnaire completed at study entry (1995-1996) with the MyPyramid Equivalents Database (version 1.0). Other variables included energy, nutrients, multivitamins, and alcohol. Models were stratified by sex and adjusted for age, ethnicity, education, body mass index, smoking, physical activity, and menopausal hormone therapy (in women). During 5 years of follow-up, 3,110 incident colorectal cancer cases were ascertained. Although the indexes differ in design, a similarly decreased risk of colorectal cancer was observed across all indexes for men when comparing the highest scores with the lowest: Healthy Eating Index-2005 (relative risk (RR) = 0.72, 95% confidence interval (CI): 0.62, 0.83); Alternate Healthy Eating Index (RR = 0.70, 95% CI: 0.61, 0.81); Mediterranean Diet Score (RR = 0.72, 95% CI: 0.63, 0.83); and Recommended Food Score (RR = 0.75, 95% CI: 0.65, 0.87). For women, a significantly decreased risk was found with the Healthy Eating Index-2005, although Alternate Healthy Eating Index results were similar. Index-based dietary patterns that are consistent with given dietary guidelines are associated with reduced risk.

Effects of 6 vs 3 eucaloric meal patterns on glycaemic control and satiety in people with impaired glucose tolerance or overt type 2 diabetes: A randomized trial.

BACKGROUND/OBJECTIVES: The study aimed to compare the effects of two eucaloric meal patterns (3 vs 6 meals/day) on glycaemic control and satiety in subjects with impaired glucose tolerance and plasma glucose (PG) levels 140-199mg/dL at 120min (IGT-A) or PG levels 140-199mg/dL at 120min and >200mg/dL at 30/60/90min post-oral glucose load on 75-g OGTT (IGT-B), or overt treatment-naïve type 2 diabetes (T2D). SUBJECTS/METHODS: In this randomized crossover study, subjects with IGT-A (n=15, BMI: 32.4±5.2kg/m2), IGT-B (n=20, BMI: 32.5±5kg/m2) or T2D (n=12, BMI: 32.2±5.2kg/m2) followed a weight-maintenance diet (45% carbohydrates, 20% proteins, 35% fats) in 3 or 6 meals/day (each intervention lasting 12 weeks). Anthropometrics, diet compliance and subjective appetite were assessed every 2 weeks. OGTT and measurements of HbA1c and plasma lipids were performed at the beginning and end of each intervention period. RESULTS: Body weight and physical activity levels remained stable throughout the study. In T2D, HbA1c and PG at 120min post-OGTT decreased with 6 vs 3 meals (P<0.001 vs P=0.02, respectively). The 6-meal intervention also improved post-OGTT hyperinsulinaemia in IGT-A subjects and hyperglycaemia in IGT-B subjects. In all three groups, subjective hunger and desire to eat were reduced with 6 vs 3 meals/day (P<0.05). There were no differences in HOMA-IR or plasma lipids between interventions. CONCLUSION: Although weight loss remains the key strategy in hyperglycaemia management, dietary measures such as more frequent and smaller meals may be helpful for those not sufficiently motivated to adhere to calorie-restricted diets. Our study shows that 6 vs 3 meals a day can increase glycaemic control in obese patients with early-stage T2D, and may perhaps improve and/or stabilize postprandial glucose regulation in prediabetes subjects.

Treatment of bendamustine and prednisone in patients with newly diagnosed multiple myeloma results in superior complete response rate, prolonged time to treatment failure and improved quality of life compared to treatment with melphalan and prednisone--a randomized phase III study of the East German Study Group of Hematology and Oncology (OSHO).

PURPOSE: This randomized phase III study compared bendamustine and prednisone (BP) to standard melphalan and prednisone (MP) treatment in previously untreated patients with multiple Myeloma (MM). PATIENTS AND METHODS: To be included, patients had to have histologically and cytologically proven stage II with progressive diseases or stage III MM. They were randomly assigned to receive BP (n=68) or MP (n=63). The primary endpoint was the time to treatment failure (TTF). Secondary endpoints included survival, remission rate, toxicity and quality of life. RESULTS: The overall response rate was 75% in the BP and 70% in the MP group. A significantly higher number of patients treated with BP achieved a complete remission than did patients receiving MP (32 vs. 13%; P=0.007), and the maximum response was achieved more rapidly in patients treated with BP compared to those receiving MP (6.8 vs. 8.7 cycles; P<0.02). TTF and remission duration were significantly longer in the BP group. Patients receiving BP had higher QoL scores and reported pain less frequently than patients receiving MP. CONCLUSION: BP is superior to MP with respect to complete remission rate, TTF, cycles needed to achieve maximum remission and quality of life and should be considered the new standard in first-line treatment of MM patients not eligible for transplantation.

Effect of meal frequency on glucose and insulin levels in women with polycystic ovary syndrome: a randomised trial.

BACKGROUND/OBJECTIVES: The aim of the study was to compare the effect of two-meal patterns (three vs six meals per day) on glucose and insulin levels in women with polycystic ovary syndrome (PCOS). SUBJECTS/METHODS: In a randomised, crossover, 24-week study, 40 women with PCOS, aged 27±6 years, body mass index 27±6 kg/m(2), followed a weight maintenance diet (% carbohydrates:protein:fat, 40:25:35), consumed either as a three- or a six-meal pattern, with each intervention lasting for 12 weeks. Anthropometric measurements, diet compliance and subjective hunger, satiety and desire to eat were assessed biweekly. All women underwent an oral glucose tolerance test (OGTT) with 75 g glucose for measurement of plasma glucose and insulin at the beginning and end of each intervention. HaemoglobinA1c (HbA1c), blood lipids and hepatic enzymes were measured at the beginning and end of each intervention. RESULTS: Body weight remained stable throughout the study. Six meals decreased significantly fasting insulin (P=0.014) and post-OGTT insulin sensitivity (Matsuda index, P=0.039) vs three meals. After incorporation of individual changes over time, with adjustment for potential confounders, the only variable that remained significant was the Matsuda index, which was then used in multivariate analysis and general linear models. Six meals improved post-OGTT insulin sensitivity independently of age and body weight vs three meals (P=0.012). No significant differences were found between six and three meals for glucose, HbA1c, blood lipids, hepatic enzymes, subjective desire to eat and satiety. CONCLUSIONS: Six meals had a more favourable effect on post-OGTT insulin sensitivity in women with PCOS compared with isocaloric three meals.

The expression of the Wilms' tumor gene in acute myelocytic leukemias as a possible marker for leukemic blast cells.

The Wilms' tumor gene (wt-1) is expressed in the developing fetal kidney, gonads and in Wilms' tumors. Recently, the expression of wt-1 in leukemia-derived cell lines and cases of acute leukemias (AL) was reported. The present study was designed to investigate the potential of wt-1 as genetic marker for acute myelocytic leukemias (AML). Blast cells from 52 patients with AML, 14 patients in complete remission (CR) and four leukemic cell lines were examined for expression of wt-1 mRNA. Peripheral blood mononuclear cells (PBMNC) and bone marrow (BM) from 13 healthy persons were used as negative controls. RNA of the wt-1 gene was expressed in 41/52 (79%) patients with previously untreated AML. The majority of the 14 patients studied in CR lost wt-1 expression. In three out of the four patients in CR reappearance of wt-1 expression preceded relapse of the disease. In three of the four tested cell lines wt-1 specific transcription was demonstrated. No correlation to FAB classification, immunophenotype or response to treatment was found. Our experiments indicate wt-1 expression in the majority of AML, but not in bone marrow or PBMNC of healthy controls. Therefore, wt-1 expression may be associated with the presence of malignant blast cells and the analysis of wt-1 gene expression via PCR may be a sensitive method for the detection of leukemic blast cells.

GM-CSF in a double-blind randomized, placebo controlled trial in therapy of adult patients with de novo acute myeloid leukemia (AML).

We investigated whether GM-CSF given concomitantly with chemotherapy (CT) and thereafter, improves the outcome of adults with de novo AML by increasing the efficacy of CT and reducing infections. CT included Ara-C, daunorubicin and etoposide (DAV) for induction and early consolidation therapy and one cycle with high-dose (patients aged < or = 50 years) or intermediate dose Ara-C (patients aged > 50 years)/daunorubicin for late consolidation therapy. Eight patients were randomized after DAVI to receive either GM-CSF (E. coli, 250 micrograms/m2/day, s.c.) or placebo starting 48 h prior to DAVII and the subsequent courses and given throughout CT until the absolute neutrophil count had recovered to > 500/microliters. The CR rate was 81% in the GM-CSF and 79% in the placebo group (p = 0.57; Fisher's exact test). The probability of relapse-free survival at 41 months after a median follow-up of 35 months was 42% in the GM-CSF and 41% in the placebo group (p = 0.89; log rank test). GM-CSF did not shorten the period of neutropenia < or = 500/microliters, while it prolonged the duration of thrombocytopenia < or = 25,000/microliters. The incidence and severity of infections as well as the non-hematological toxicity were similar in both groups. In summary, in this randomized trial GM-CSF as an adjunct to AML therapy was feasible. For the present GM-CSF does not have a significant effect on treatment outcome.

Establishment and characterization of a new, factor-independent acute myeloid leukemia line designated Ei501.

We established a factor-independent acute myeloid leukemia cell line, designated Ei501. The line has been growing in RPMI 1640 media for 18 months and can be maintained without addition of growth factors. Ei501 is positive for myeloperoxidase and negative for esterase and PAS. Cytogenetic analysis revealed the FAB M3 associated t(15;17) translocation and a translocation of the chromosomes 7 and 8: 46 XX, -7, +t(7;8)(q32;q13), t(15;17)(q22;q12). This karyotype was confirmed by fluorescence in situ hybridization. Ei501 cells express AML-associated surface markers such as CD13, CD33 and CD38. Although 42% of the patient's blast cells were CD34-positive, the line lacks surface expression of CD34. Furthermore the line has a number of characteristics which are detectable in blasts from AML patients, such as surface adhesion molecules, cytokines such as TGF-beta, cytokine receptors such as the IL-2 receptor beta and gamma chains or the IL-4 receptor and the genes for the transcription factor wt-1 (Wilms' tumor gene) and for the proto-oncogene bcl-2, both shown to be present in the majority of patients with AML. Additionally the line can be used as target in cytotoxicity assays using IL-2 activated cytotoxic lymphocytes as effector cells. In conclusion, besides a rare karyotype the Ei501 cell line has several features common in AML, and may therefore be used as a model to study pathogenetic mechanisms in acute myeloid leukemia.

The inhibition of lymphokine-activated killer cells in acute myeloblastic leukemia is mediated by transforming growth factor-beta 1.

In acute myeloblastic leukemia (AML), the T cell response and cytotoxic activity are impaired at time of diagnosis due to not-yet-identified soluble immunosuppressing factors. The inhibition of autologous antileukemic immune response by these factors may support immunosurveillance of AML. A well-known inhibitor of lymphokine-activated killer (LAK) cell activity is transforming growth factor-beta 1 (TGF-beta 1). To evaluate the possible significance of TGF-beta 1 for the impaired cytotoxic activity in AML at time of diagnosis, we looked for the TGF-beta 1-specific mRNA, for the production and release of TGF-beta 1, and for its relevance for immunosuppressing activities in AML. In the culture supernatants of 18 investigated AMLs, we detected various amounts of TGF-beta protein. The TGF-beta 1 and TGF-beta 2 protein concentrations were 105 pg/mL (< 50-240 pg/mL) and 32 pg/mL (< 2-91 pg/mL), respectively. In 13 of 15 patients, the leukemic blasts expressed TGF-beta 1 mRNA. To exclude possible interferences with contaminating mononuclear cells (MNC), the data were confirmed by analysis of sorted blast cells and leukemic cell lines. All investigated leukemic cell lines expressed TGF-beta 1 protein and mRNA. The culture supernatants of AMLs inhibited LAK activity strongly in a dose-dependent manner. The inhibition of cytotoxicity could be restored by the addition of neutralizing TGF-beta 1 antibodies. The data suggest TGF-beta 1 to be a relevant factor for the inhibition of cytotoxic activities in AMLs.

The Wilms' tumor gene is expressed in a subset of CD34+ progenitors and downregulated early in the course of differentiation in vitro.

The Wilms' tumor gene (wt1) is strongly expressed in malignant blasts of acute myeloid leukemia (AML) in approximately 80% of all cases. However, the role of wt1 expression in non malignant hematopoietic cells remains unclear. To characterize the expression of wt1 in differentiating hematopoietic progenitors, we isolated and cultured CD34+ progenitor cells from four healthy bone marrow donors with stem cell factor (SCF) and granulocyte colony stimulating-factor (G-CSF) to induce differentiation into granulocytes. Four different cultures were carried out for 12 days. During culture, wt1 mRNA expression was analyzed by defining its ratio relative to beta-actin using reverse transcriptase polymerase chain reaction (RT-PCR). To monitor the stage of differentiation, expression of cell surface markers and peroxidase was analyzed daily. The initial purity of CD34+ cells ranged between 80% and 90%; after 12 days, the frequency of neutrophil bands and segmented neutrophils was approximately 60%. Using RT-PCR to determine the ratio of wt1 to beta-actin expression, we reproducibly detected maximum expression of wt1 mRNA at day 0 in two cultures and at day 1 in two other CD34+ cell cultures; at both these time points nearly all cells fulfilled the morphological and immunephenotypical criteria of early hematopoietic blast cells. Wt1 expression dropped rapidly at day 1 and 2, respectively, in these two pairs of cultures, and was accompanied by an increase of cells expressing CD33 surface antigen. Our data suggest that wt1 expression is restricted to a subset of CD34+ progenitors and downregulated in later stages of differentiation in vitro.

The role of acetic acid on glucose uptake and blood flow rates in the skeletal muscle in humans with impaired glucose tolerance.

BACKGROUND/OBJECTIVES: Previous studies support the glucose-lowering effect of vinegar. However, the effect of vinegar on muscle glucose metabolism and endothelial function has not been studied in humans. This open, randomized, crossover, placebo-controlled study aims to investigate the effects of vinegar on muscle glucose metabolism, endothelial function and circulating lipid levels in subjects with impaired glucose tolerance (IGT) using the arteriovenous difference technique. SUBJECTS/METHODS: Eight subjects with IGT (4 males, age 46±10 years, body mass index 30±5) were randomised to consume 0.50 mmol vinegar (6% acetic acid) or placebo before a mixed meal. Plasma samples were taken for 300 min from the radial artery and the forearm vein for measurements of glucose, insulin, triglycerides, non-esterified fatty acids (NEFAs) and glycerol. Muscle blood flow was measured with strain gauge plethysmography. Glucose flux was calculated as the arteriovenous difference of glucose multiplied by the blood flow rates. RESULTS: Vinegar compared with placebo: (1) decreased arterial plasma insulin (Poverall<0.001; P75 min=0.014, ß=-42), (2) increased forearm blood flow (Poverall<0.001; P240 min=0.011, ß=1.53; P300 min=0.023, ß=1.37), (3) increased muscle glucose uptake (Poverall<0.001; P60 min=0.029, ß=2.78) and (4) decreased arterial plasma triglycerides (Poverall=0.005; P240 min<0.001, ß=-344; P300 min<0.001, ß=-373), without changing NEFA and glycerol. CONCLUSIONS: In individuals with IGT, vinegar ingestion before a mixed meal results in an enhancement of muscle blood flow, an improvement of glucose uptake by the forearm muscle and a reduction of postprandial hyperinsulinaemia and hypertriglyceridaemia. From this point of view, vinegar may be considered beneficial for improving insulin resistance and metabolic abnormalities in the atherogenic prediabetic state.

Kaposi's sarcoma in HIV infection: impact on opportunistic infections and survival.

OBJECTIVE: To determine the effect of Kaposi's sarcoma on survival of HIV-infected patients. METHODS: Retrospective cohort study to compare the survival of 241 HIV-infected homosexual patients with Kaposi's sarcoma (cases) with that of 241 HIV-infected homosexual patients without Kaposi's sarcoma (control subjects) but with a similar level of immunosuppression (measured by the absolute CD4+ lymphocyte count). RESULTS: Cases and control subjects were similar in age, occurrence of previous opportunistic infections, and the use of antiretroviral therapy. The mean CD4+ lymphocyte counts were similar for cases and control subjects (185 x 10(6) versus 184 x 10(6)/l, respectively). Cases had a higher incidence of opportunistic infections (5.95 versus 3.88 infections, respectively, per 100 person-months of observation) and a greater number of infections typical of late-stage HIV infection. Cases had a shorter overall survival than did control subjects (P=0.0025). Kaposi's sarcoma was associated with an increased risk of death (odds ratio, 1.28), even when adjusting for age, previous opportunistic infection, baseline CD4+ lymphocyte count, and antiretroviral therapy. CONCLUSION: Kaposi's sarcoma appears to accelerate the clinical course of HIV infection. Opportunistic infections develop earlier and more often in patients with the disease than in control subjects. Survival was significantly shorter in patients with Kaposi's sarcoma.

Rapid cytokine release in cancer patients treated with interleukin-2.

Serum concentrations of interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-6 (IL-6), interleukin-1 (IL-1) and interferon-alpha (IFN-alpha) were determined by commercially available enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay (RIA) in cancer patients treated with recombinant IL-2 (rIL-2) either as 1-h infusion (3 or 5 x 10(6)/m2) or continuous intravenous infusion for 5 days (3 x 10(6)/m2/day). A significant increase of TNF-alpha and IL-6 serum levels was observed in each patient. One-hour infusion of IL-2 induced a very rapid secretion of TNF-alpha, IL-6 and IFN-gamma with considerably higher peak levels than during IL-2 continuous intravenous infusion. IFN-gamma was released into the blood of all patients receiving IL-2 1-h infusion, but only occasionally during or after IL-2 continuous intravenous infusion. Neither IFN-alpha nor IL-1 were detectable in the serum before, during, or following IL-2 treatment in all patients studied. The kinetics of IL-2 after 1-h infusion fitted to a two-compartment model, suggesting the synthesis of considerable amounts of endogenous IL-2. Following IL-2 1-h infusion, rising TNF-alpha serum levels preceded the increase of serum IFN-gamma or IL-6. The serum peak levels of IFN-gamma and IL-6 decreased rapidly with a half-life of 0.29 to 2.5 h. The concentration time profiles of TNF following 1-h infusion of IL-2 demonstrated a considerably longer half-life than that of intravenously administered recombinant TNF as done in other studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Metoclopramide kinetics at high-dose infusion rates for prevention of cisplatin-induced emesis.

Eleven male subjects aged 24 to 58 yr received cisplatin, 90 to 120 mg/m2 iv, in combination with other cytostatic drugs such as doxorubicin HCl and bleomycin. To prevent emesis, two high-dose metoclopramide regimens were started 2 hr before cytostatic therapy. Regimen A (n = 7) consisted of a loading dose infusion of 1 mg/kg/hr over 2 hr, followed by a maintenance infusion of 0.5 mg/kg/hr over 24 hr (total dose was 14 mg/kg in each cytostatic cycle). Regimen B (n = 6) consisted of half the metoclopramide dose. The following kinetics were derived from the metoclopramide steady-state plasma levels and the t1/2 of the elimination phase 26 to 38 hr after dosing (median value and range are listed): Steady-state plasma concentration in group A and group B was 750 (480 to 1520) and 360 (300 to 480) ng/ml plasma. Drug clearance in group A and group B was 0.67 (0.3 to 1.0) and 0.70 (0.5 to 0.8) l/hr/kg. Volumes of drug distribution in group A and group B were 4.4 (1.9 to 6.5) and 4.3 (3.2 to 5.9) l/kg. Values for the t1/2 in the elimination phase in group A and group B were 4.7 (3.0 to 5.4) and 4.3 (3.7 to 5.1) hr. It appears that metoclopramide kinetics at high doses were dose linear, i.e., without evidence of cumulation. There were few side effects; vomiting was effectively suppressed by both regimens.

Recombinant human granulocyte-macrophage colony-stimulating factor after combined chemotherapy in high-grade non-Hodgkin's lymphoma--a randomised pilot study.

High-grade non-Hodgkin's lymphomas (NHL) can potentially be cured with combination chemotherapy, although the optimum schedules still have to be defined. Clinical trials with intensive chemotherapy are predominantly limited by myelosuppression. Here, haematopoetic growth factors open up the possibility of reducing chemotherapy-associated toxicities. In this randomised pilot study, we investigated the effects of a recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) following combined chemotherapy with vincristine, doxorubicin, cyclophosphamide, prednisone and etoposide (VACPE). A total of 35 patients with high-grade NHLs were randomised to receive either rhGM-CSF or placebo during the first two chemotherapy cycles and rhGM-CSF for all following cycles. rhGM-CSF was administered at a dosage of 5 micrograms/kg for 10 days or until neutrophils were > 1/nl following chemotherapy. The analyses revealed a significant reduction of neutropenia and duration of neutropenia in the rhGM-CSF group. Adverse events were rare and generally mild apart from one anaphylactoid reaction. No effects of rhGM-CSF were observed concerning the platelet nadir or duration of thrombocytopenia. The benefit of rhGM-CSF for response induction and survival via rhGM-CSF-supported dose intensification remains to be determined.

Reduced-dose cladribine (2-CdA) plus mitoxantrone is effective in the treatment of mantle-cell and low-grade non-Hodgkin's lymphoma.

Cladribine (2-chlorodeoxyadenosine) (2-CdA) has been shown to be effective in mantle-cell (MCL) and low-grade lymphomas (lgNHL). The aim of this multicentre study was to evaluate the rate and duration of remissions and to examine the toxicity of the combination of reduced-dose 2-CdA and mitoxantrone (CdM) in MCL and lgNHL as first-line therapy or for patients in their relapse. A total of 285 courses, median of five courses per patient, were administered to 62 evaluable patients (42 previously untreated, 20 relapsed) with 5 mg/m(2) 2-CdA per day given as an intermittent 2-h infusion over 3 consecutive days combined with 8 mg/m(2) mitoxantrone on days 1 and 2 for the untreated patients or 12 mg/m(2) mitoxantrone on day 1 for patients in their first relapse for a maximum of six cycles every four weeks. 32 follicular, 18 MCL, 9 lymphoplasmacytoid, 2 marginal zone and 1 unclassified low-grade B-cell lymphoma were involved in the study. 56 of the 62 patients responded to CdM resulting in an overall response rate of 90% (95% confidence interval (CI), 80-96%) with a complete remission (CR) rate of 44% (95% CI, 31-57%) and a median duration of remission of 25 months (range 6-42+). The overall survival rate at 48 months was 80%. For 42 previously untreated patients, the overall response rate was 88% (95% CI, 74-96%) with a CR rate of 38% (95% CI, 24-54%), whereas the response rate for the group of 20 previously treated patients was similar with a 95% overall response (95% CI, 75-100%) and a CR rate of 55% (95% CI, 32-77%). In MCL, CdM showed a high activity, achieving a response rate of 100% (95% CI, 81-100%) with a CR rate of 44% and a median duration of remission of 24 months (range 6-35+). Myelosuppression was the major toxicity with 23% grade 3 granulocytopenia and 50% grade 4. Thrombocytopenia was less commonly observed, with only 8% grades 3 and 4. These results demonstrate that the combination of reduced-dose 2-CdA and mitoxantrone is a highly active regimen in the treatment of low-grade lymphomas, and in particular of MCL.